1. Field of the Invention
This invention relates to controlled release drug delivery system which provides constant release of therapeutic agent by maintaining a constant surface area. Oral controlled release delivery, rumen bolus, sublingual, and buccal applications are indicated for a broad spectrum of drugs.
2. Description of Related Art
A number of devices have been developed for the sustained release of active medicament. Monolithic systems, where the drug is dispersed in a polymer matrix that is permeable to the drug, have been appealing because of their ease of manufacture. U.S. Pat. No. 4,369,172; U.S. Pat. No. 3,870,790; U.S. Pat. No. 4,357,469; U.S. Pat. No. 4,226,849; U.S. Pat. No. 3,590,117; U.S. Pat. No. 4,389,393; G.B. 2 053 682; U.S. Pat. No. 4,309,405; U.S. Pat. No. 4,309,406; U.S. Pat. No. 4,167,558; U.S. Pat. No. 4,259,314; and U.S. Pat. No. 3,065,143 are a few of the many examples in this category. U.S. Pat. No. 3,402,240; U.S. Pat. No. 3,062,720, and U.S. Pat. No. 3,456,049 represent sustained release tablets in which the drug is imbedded in an insoluble matrix. Drug release rates from these types of monolithic devices generally decline with time (T. Higuchi, J. Pharm. Sci., 50,874 (1961); T. J. Roseman, J. Pharm. Sci., 61,46 (1972); and H. K. Lonsdale, R. W. Baker, "Controlled Release of Biologically Active Agents", Ed. A. C. Tanquary, Plenum Press, N.Y. (1974)). These delivery systems also require relatively large amounts of excipients to maintain tablet integrity and produce the desired drug release rate. An Alza device, U.S. Pat. No. 3,926,188, consisting of a three layer laminate drug dispenser with a core of crystalline drug of low water solubility dispersed in homogeneous polymer matrix, also has a permeable rate controlling polymer coating. Medicament is not released at a constant rate, instead dissolution profiles show a strong initial burst effect, which may lead to toxicity with many drugs.
One of the major goals of formulators of sustained release pharmaceuticals has long been to provide an approximately constant rate of drug release over an extended period of time. European Patent Application 84401152.8 (Publication No. 0 131 485); Derwent 85-019972/04) claims to have achieved constant drug release by a controlled surface erosion mechanism. This rather cumbersome, multi-component oral delivery system includes: 1) 10-90% drug (with water solubility of 1/5 to 1/1000); 2) 1-40% surface controlling compound; 3) 0.05-1% surface activator; 4) 0.1-2% surfactant. Tablets are either spherical or have a thickness/diameter ratio that permits tablet erosion and penetrant control sufficient for controlled surface erosion.
A second method for generating zero-order release is to maintain a constant tablet surface area, available for dissolution. UK Patent Application GB 2 078 518 (Derwent 85413 D/47); U.S. Pat. No. 4,465,660 (Derwent 84-218985/35); and U.S. Pat. No. 4,547,358 (Derwent 88-355419/50) detail oral drug delivery systems specifically for theophylline. The tablets are uncoated, non-disintegrating, have flat surface, and contain 94.8-99% theophylline. "Relatively steady" release rates are obtained by severely restricting tablet thickness to 0.08-0.12 in. Constant release, however, is not maintained since the surface area of the tablet decreases with time.
Another technique of producing constant release of therapeutic agent utilizes one or more apertures extending partially or completely through the tablet. U.S. Pat. No. 3,113,076; U.S. Pat. No. 4,217,898; U.S. Pat. No. 3,146,169; G.B. 1 372 040; and U.S. Pat. No. 4,218,433 exemplify this type of delivery system. As the outer surface area of these tablets decreases with time, the surface area created by the dissolving aperture(s) increases, keeping the total tablet surface area fairly constant. Others have tried to achieve constant release rates by covering the tablet partially or totally with slowly dissolving materials. Japanese patent J6 2053 918 (Derwent 87-105812/15) claims a sustained release tablet with a core of disintegrating substance (that is harmful to the stomach and has a bad taste) buried completely in the inner core of the tablet, which has a thickness twice or less the thickness of the outer part of the tablet. Uniform drug release rates are not obtained. Constant medicament surface area is maintained in J6 1243016 Derwent 86-328111/50), by the use of a ring core of active substance and an outer ring portion that dissolves at the same slow rate as the inner drug core specified to be twice the outer ring width. Broad application of this system would prove to be difficult and time consuming, attempting to match polymer dissolution rates to each drug used.
Australian Patent Application 27462/63 (Derwent 12045) relates to anti-aphthous preparations and describes a vaccine implant device having an oblong body that is protected by a moisture-repelling surface layer except at one end or at both ends. The vaccine substance (in powdered form) is homogeneously mixed with a finely divided inert resorbable vehicle (for example, cholesterol, stearic acid or zinc oxide), compressed and coated (except at free access surfaces) so that it is gradually reabsorbed together with the other components of the body from the moment of its implantation in an animal until its complete reabsorption. It is disclosed that this period of time may be extended to three to five years.
European Patent Application 88304974.4 (Publication No. 0 294 993) describes a controlled drug delivery system which comprises one or more active substances homogeneously dispersed, with or without inert excipients, and contained substantially in the space of a tablet or bolus by means of an all-covering essentially impermeable wall or coating (for example ethylene-vinyl acetate) except for one or more strips of removed wall or coating from the side of said devices. A substantially constant rate (i.e. zero-order) of release is disclosed. The surface area available for dissolution does not necessarily remain constant since the bolus can have inert or dissolvable ingredients. Since only a minute portion of the surface is available for dissolution, release rates are very slow (the fastest shown was 70% dissolved in 35 days). The application of this system to most conventional oral sustained release formulations would be impossible.